1. Field of the Invention
The present invention relates generally to the fields of cardiovascular pharmacology and therapeutics, and animal nutrition. More specifically, the present invention relates to a method of decreasing plasma homocysteine levels in animals with hyperhomocyst(e)inemia. This invention also relates to a method of reducing or eliminating the supplemental methionine, choline, and betaine routinely added to animal feeds.
2. Description of the Related Art
Pharmaceutical or nutriceutical applications of the invention. Cardiovascular disease (CVD), i.e., coronary, cerebral, and peripheral atherosclerosis and thrombosis, is the major cause of death in the United States. The age-adjusted death rate from CVD decreased about 40 percent from 1964 to 1985 (1). This decline was attributed to better health care and lifestyle changes. Despite this decline, more than one fourth of all Americans still suffer from some form of CVD, and almost 50% die of this disease (2). The cost of CVD to Americans in direct health care expenditures and lost productivity is estimated to be $110 billion each year (2). This cost estimate is expected to rise since the population of elderly in this country is increasing.
The cause of CVD is multifactorial. Some well known risk factors include hypertension, smoking, and high blood cholesterol. Many risk factors are influenced by genetic predisposition and diet. It has been shown that hyperhomocyst(e)inemia is associated with the premature development of CVD (3, 4). Furthermore, there is evidence that suggest that the relationship between plasma homocysteine and CVD is causal and not just a marker for another risk factor since vascular lesions have been induced in primates by infusing homocysteine for a 3 month period. The risk of fatal thrombosis is reduced in homocystinurics undergoing plasma homocysteine-lowering treatment.
Fasting plasma homocysteine levels have been classified as either, normal (10-15 .mu.M), or one of the following levels of hyperhomocyst(e)inemia; moderate (15-30 .mu.M), intermediate (31-100 .mu.M), or severe (&gt;100 .mu.M). Like blood cholesterol, the relationship of plasma homocysteine to CVD appears to be graded (5). This means that any increase in plasma homocysteine above normal is associated with an increased risk, and that the higher the elevation, the greater the risk. Several nutritional and genetic determinants have been identified that cause hyperhomocyst(e)inemia and some of these determinants are more common than previously imagined. The mechanistic details of how elevations in plasma homocysteine promote CVD is not completely understood.
Epidemiological reports indicate that 15-40% of CVD patients have elevated levels of plasma homocysteine (6). Studies have shown associations of plasma homocysteine with age, sex, smoking, hypertension, and total serum cholesterol (3, 4, 7). Plasma homocysteine increases with age and is higher in males than females. There is a positive linear association between plasma homocysteine and serum cholesterol levels. Both smoking and hypertension have multiplicative effects on plasma homocysteine (7).
The association of hyperhomocyst(e)inemia with some of the most potent risk factors for CVD, such as smoking, hypertension, and cholesterol metabolism, makes managing the levels of plasma homocysteine an important public health goal. An effective dietary or pharmaceutical treatment for hyperhomocyst(e)inemia would be expected to decrease the mortality and morbidity from CVD and result in considerable health care savings.
One of the most effective treatments for severe hyperhomocyst(e)inemia is the oral administration of pharmacological doses of betaine, either alone, or concurrent with vitamin supplementation. Betaine, a metabolite of choline oxidation, is a substrate for an enzyme called betaine-homocysteine methyltransferase. Betaine-homocysteine methyltransferase catalyzes the conversion of betaine and homocysteine to dimethylglycine and methionine, respectively. The treatment of hyperhomocyst(e)inemia with betaine reduces plasma homocysteine by increasing the conversion of homocysteine to methionine via the betaine-homocysteine methyltransferase catalyzed reaction. Normal levels of plasma homocysteine, however, are rarely attained by this treatment leaving considerable CVD risk for these individuals.
Animal feed applications relating to methionine. The animal feed industry typically formulates protein-containing organic feeds for domestic animal consumption. These feeds are often supplemented with various nutrients so that they meet the specific dietary requirements of a given animal species and therefore improve some measure of animal performance. Animal performance being defined herein as including but not limited to the physiological states of growth, gestation, and lactation.
Many feeds contain corn or soybean meal, or a mixture of these two feedstuffs, as a base ingredient. These feeds are routinely supplemented with methionine and choline to meet the recommended dietary intakes of these compounds (8-10). For example, methionine is typically added to these practical diets because they are often deficient in this essential amino acid. Choline also is added to these feeds. Although most animals do not have an absolute requirement for choline, and one notable exception is the chicken, choline is routinely added to animal feeds because it has methionine-sparing effects, that is, it reduces an animals dietary requirement for methionine. Betaine, a metabolite of choline oxidation, also is added to feeds for methionine- and choline-sparing effects. Some studies suggest that dietary betaine can reduce carcass fat in pigs and chickens and is effective in the treatment of diarrhea and wet litter in fowl.
In summary, the prior art is deficient in the lack of an effective methods to decrease plasma homocysteine levels in animals with hyperhomocyst(e)inemia. In addition, the prior art is deficient in a method to maximize the conversion of homocysteine to methionine while simultaneously decreasing the level of dietary methionine, choline and betaine added to animal feeds necessary to obtain optimal animal performance. The present invention fulfills this long-standing need and desire in the art.